Age-related disorders including Alzheimer's disease affect an estimated 4.5 mlllion Americans. National direct and indirect annual costs of caring for individuals with Alzheimer's disease are at least $100 billion, according to estimates used by the Alzheimer's Association and the National Institute on Aging. Parkinson's disease affects over 1 million people in the US alone and is one of the most common debilitating diseases in the country. According to the National Parkinson's Foundation, each individual spends an average of $2,500 a year for medications. Estimates of costs of medical care, disability payments and lost income exceed $5.6 billion annually. Thus, age-related disorders have a significant impact and understanding the aging process may help develop new therapies for these and other disorders.
Multiple contributions to aging and lifespan regulation in animals have been proposed, including accumulation of oxidatively damaged macromolecules, shortened telomeres, progeny production, metabolic rate, caloric intake, and the existence of an aging program that acts as a timing mechanism (Tissenbaum, H. A. and L. Guarente, (2002) Dev Cell, 2(1), 9-19). The ease of genetic analysis and modest life span of Caenorhabditis elegans (C. elegans) has made it the multicellular organism of choice for the investigation into the genetic basis of aging and longevity.
The C. elegans insulin/IGF-1-like signaling pathway is the best-characterized pathway modulating aging, and single gene mutations in this pathway have been shown to significantly affect lifespan. For example, loss of function (lf) mutations in daf-2, the insulin/IGF-1 receptor homolog, cause the animal to live twice as long as wild-type animals (Kenyon, C., et al., (1993) Nature, 366(6454), 461-4). Many molecular studies have shown that DAF-2 activates a phosphatidylinositol-3-OH (PI3K) signaling cascade, which ultimately acts to antagonize the DAF-16 forkhead family transcription factor. DAF-16 is then unable to repress genes that regulate longevity, as well as the dauer diapause decision and stress response, and to activate genes that are required for metabolism and reproductive growth.
While many factors that regulate aging in C. elegans have been identified, it is apparent that the global genetic patterns required for lifespan determination have not yet been completely defined. Changes in gene expression in aged adults across species do not solely seem to be implemented in response to mounting damage; rather, conserved, developmentally timed transcriptional regulation during young adulthood seems to control features of aging (McCarroll, S. A., et al. (2004) Nat Genet, 36(2), 197-204). For example, young adult C. elegans and Drosophila animals turn off a conserved battery of oxidative respiration genes and turn on stress response genes. A similar trend is seen in human brain tissue, where the switch occurs at around age 40 (Lu, T., et al., (2004) Nature, 429(6994), 883-91). This implies that aging, or more specifically the time of death, is under temporal control at the genetic level.
It is an object of the present invention to provide genes involved in senescence, aging or age-related disorders which can be used as drug targets or in drug design for compounds decreasing one or more characteristics of aging.
It is another object of the present invention to provide inhibitory compositions, including nucleic acid molecules such as miRNAs, for inhibition of expression of one or more genes involved in senescence, aging, or age-related disorders.
It is further an object of the present invention to provide nucleic acids for diagnosis, treatment or prophylaxis of one or more symptoms of senescence, aging, or age-related disorders.